COMET: Concordance in MRI and Pathology Diagnosis of Extranodal Tumour Deposits

Sponsor

Royal Marsden NHS Foundation Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT03303547

Collaborator

Pelican Cancer Foundation (Other)

100

Enrollment

Location

Arm

72.5

Anticipated Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Predicting prognosis in rectal cancer and determining indications for neoadjuvant treatment is an ongoing challenge for colorectal multidisciplinary teams (MDTs). Staging is almost universally based on the TNM system which, despite multiple changes and increasing levels of sub-classification and complexity, is still flawed in its ability to stratify patients and predict prognosis(1-3). Determining which patients will benefit most from neoadjuvant and adjuvant therapy is still controversial; NICE guidelines are open to interpretation(4) and there is significant geographic variation in the way patients are managed. The Aim of this study is to prove the accuracy of MRI diagnosis of ENTD and its adverse effect on prognosis.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Rectum	Diagnostic Test: MRI mapping to guide pathological sampling of extranodal tumour deposits	N/A

Detailed Description

This will be a prospective interventional, multi-centre study. Patients will be identified from multidisciplinary team meetings. All patients presenting with primary adenocarcinoma of the rectum and undergoing resectional surgery (with or without prior neo-adjuvant treatment) will be eligible for inclusion in the study. Patients will be approached following the MDT at their pre-op clinic and asked to participate in the trial. If they agree, they will be asked to sign a consent form before surgery.

Local Radiologists will be asked to complete a study Imaging CRF for the baseline MRI scan, and post-preoperative treatment MRI scan, if applicable, which will include standard staging information and, additionally, information on the presence of Tumour Deposits (mrTD). (Before site initiation, local study Radiologists will be offered training in identifying mrTDs and asked to complete an assessment for quality assurance purposes.)

Prior to surgery, imaging CRFs and pre-operative MRI scans will be sent to the Royal Marsden so that the COMET Chief Investigator (or one of her Radiology Registrars) can create an array of images and complete a central review CRF (see Figures 1 and 2) from the pre-op MRI scan. Each mrTD will be labelled (e.g E1, E2, E3). These images will be sent to the site study pathologist prior to histopathology processing of the specimen.

Histopathology

As well as following standard pathological procedures, additional sections will be taken from the area mrTD are thought to be present on MRI, and these will be kept separately from lymph nodes and clearly labelled. Deeper sections and elastin staining will only be carried out if the pathologist would do this as standard practice (i.e. it will not be requested as part of the trial). The pathologist will assess the specimen and report whether TD are present using a proforma. Tumour differentiation, CRM, T and N stage and the presence of EMVI will also be reported as standard. All pathology reporting will adhere to the Royal College of Pathologists Dataset Requirements for Reporting in Colorectal Cancer(19) to ensure standardisation between sites. A photograph of the tissue slices on a numbered grid will be sent into the Trial Office and used for mapping purposes. This should be accompanied by a completed Pathology CRF and anonymised histopathology report.

All tissue (including slides, blocks and cassettes) will be sent to the Royal Marsden COMET trial team for central review and to allow for further assessment with additional examination, staining and DNA extraction for genetic testing and KRAS, NRAS, BRAF and PIK3CA analysis. Due to the known problems with inter-observer variability in distinguishing TD from LN(17), we will attempt to objectify this by specifically asking the Study Pathologist at the Royal Marsden as well as another Pathologist at Radboud University Medical Centre in the Netherlands to identify whether any features of a LN are present for each nodule examined as well as recording the presence of vascular and neural invasion. Features which would be specific to the lesion being a LN will be given an "L" score and those which suggest a lesion of non-LN origin will be given an "E" score. If the patient subsequently presents with metastatic disease and a pathology specimen is available (either in the form of a resection or a biopsy), this will also be obtained for the same testing. Scanned-in images of slides taken from the nodules will be used for their LN assessment and central review.

Patients will undergo standard clinical follow up for a minimum of 5 years from the date of surgery. Clinic visits, imaging, blood tests and endoscopic follow-up will be carried out according to local protocols.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Concordance in MRI and Pathology Diagnosis of Extranodal Tumour Deposits

Actual Study Start Date :

Oct 16, 2017

Anticipated Primary Completion Date :

Nov 1, 2018

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MRI-Pathology N1c matching group MRI mapping will be used to guide pathologists to sample areas of the mesorectum where tumour deposits are likely to be present.	Diagnostic Test: MRI mapping to guide pathological sampling of extranodal tumour deposits Radiologist to mark areas where extranodal disease is identified on MRI. The pathologist will use this to take additional samples for analysis. This will allow better pathological staging and will affect treatment decisions for patients.

Arm

Intervention/Treatment

Experimental: MRI-Pathology N1c matching group

MRI mapping will be used to guide pathologists to sample areas of the mesorectum where tumour deposits are likely to be present.

Diagnostic Test: MRI mapping to guide pathological sampling of extranodal tumour deposits

Radiologist to mark areas where extranodal disease is identified on MRI. The pathologist will use this to take additional samples for analysis. This will allow better pathological staging and will affect treatment decisions for patients.

Outcome Measures

Primary Outcome Measures

To report the percentage prevalence of ENTD on MRI and pathology when prospective assessment and MRI mapping is carried out. [5 years]
The primary endpoint will be the percentage prevalence of ENTD on MRI compared with reported ENTD and "equivocal" nodules without evidence of LN architecture on pathology.

Secondary Outcome Measures

To measure the percentage of patients alive at 1, 3 and 5 years [1, 3 and 5 years]
1, 3 and 5-year OS and DFS will be reported in four groups of patients: ENTD+/LN+, ENTD+/LN-, ENTD-/LN+ and ENTD-/LN-. EMVI prevalence and association with ENTD, LN status, LN yield, T stage, and CRM status will also be reported. This will allow analysis of whether ENTD have independent prognostic significance when other known prognostic factors are controlled for.
To measure the percentage of patients alive and without recurrence at 1, 3 and 5 years [1, 3 and 5 years]
1, 3 and 5-year OS and DFS will be reported in four groups of patients: ENTD+/LN+, ENTD+/LN-, ENTD-/LN+ and ENTD-/LN-. EMVI prevalence and association with ENTD, LN status, LN yield, T stage, and CRM status will also be reported. This will allow analysis of whether ENTD have independent prognostic significance when other known prognostic factors are controlled for.
To measure the percentage of patients with local recurrence at 1, 3 and 5 years [1, 3 and 5 years]
1, 3 and 5-year OS and DFS will be reported in four groups of patients: ENTD+/LN+, ENTD+/LN-, ENTD-/LN+ and ENTD-/LN-. EMVI prevalence and association with ENTD, LN status, LN yield, T stage, and CRM status will also be reported. This will allow analysis of whether ENTD have independent prognostic significance when other known prognostic factors are controlled for.
To report the percentage concordance in molecular pathology between primary tumour and ENTD, LN and metastases. [5 years]
KRAS, NRAS, BRAF and PIK3CA testing will be carried out on tumour from each location. • Concordance in molecular pathology between primary tumour and ENTD, LN and metastases will be reported
To objectively record the features seen which help distinguish a LN from an ENTD and attempt to refine and clarify the definitions used in pathology. [5 years]
Lesions will be given a score which more objectively assesses the likelihood that they are of nodal or extranodal origin.
To report interobserver variation in MRI reporting by the local radiologists and the central reviewing radiologist [5 years]
Percentage agreement will be reported
To report interobserver variation in pathology reporting by the local pathologists and the central reviewing pathologist [5 years]
Percentage agreement will be reported

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients aged 18 years of age and over presenting with primary adenocarcinoma of the rectum amenable to surgical resection. This will be diagnosed on tissue biopsy and disease spread assessed on CT and MRI. Both patients having primary surgery and those undergoing neoadjuvant treatment will be included. All must have had a baseline staging MRI and those undergoing neoadjuvant therapy must also have had a post-treatment MRI.

Exclusion Criteria:

Patients with recurrent or synchronous tumours, those who are unable to have an MRI scan (e.g pacemaker, contrast allergy, severe claustrophobia) and those under the age of 18 years or unable to give informed consent will be excluded.